tbuckley/cabot-search huggingface dataset:
Targeting RNA oxidation by ISG20-mediated degradation is a potential therapeutic strategy for acute kidney injury
Authors: Meng Jia, Liang Li, Ruiqi Chen, Junyao Du, Zhe Qiao, Di Zhou, Min Liu, Xiaojie Wang, Jichao Wu, Yusheng Xie, Yu Sun, Yan Zhang, Ziying Wang, Tao Zhang, Huili Hu, Jinpeng Sun, Wei Tang, Fan Yi
Journal: Molecular Therapy (2023)

Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI. Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI.
Adenoviral vectors infect B lymphocytes in vivo
Authors: Paul J. Rice-Boucher, Samir Andrade Mendonça, Aluet Borrego Alvarez, Alexandria J. Sturtz, Reka Lorincz, Igor P. Dmitriev, Elena A. Kashentseva, Zhi Hong Lu, Rosa Romano, Mark Selby, Kunal Pingale, David T. Curiel
Journal: Molecular Therapy (2023)

B cells are the antibody-producing arm of the adaptive immune system and play a critical role in controlling pathogens. Several groups have now demonstrated the feasibility of using engineered B cells as a therapy, including infectious disease control and gene therapy of serum deficiencies. These studies have largely utilized ex vivo modification of the cells. Direct in vivo engineering would be of utility to the field, particularly in infectious disease control where the infrastructure needs of ex vivo cell modification would make a broad vaccination campaign highly challenging. In this study we demonstrate that engineered adenoviral vectors are capable of efficiently transducing murine and human primary B cells both ex vivo and in vivo. We found that unmodified human adenovirus C5 was capable of infecting B cells in vivo, likely due to interactions between the virus penton base protein and integrins. We further describe vector modification with B cell-specific gene promoters and successfully restrict transgene expression to B cells, resulting in a strong reduction in gene expression from the liver, the main site of human adenovirus C5 infection in vivo.
Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis
Authors: Masato Tamari, Lydia Zamidar, Aaron M. Ver Heul, Kristine Nograles, Joana Goncalves, Emma Guttman-Yassky, Mark Lebwohl, Brian S. Kim
Journal: Journal of Allergy and Clinical Immunology (2023)

Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD).
Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging
Authors: Robin W. Yeo, Olivia Y. Zhou, Brian L. Zhong, Eric D. Sun, Paloma Navarro Negredo, Surag Nair, Mahfuza Sharmin, Tyson J. Ruetz, Mikaela Wilson, Anshul Kundaje, Alexander R. Dunn, Anne Brunet
Journal: Nature Aging (2023)

The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.
The future of academic publishing
Authors: Abubakari Ahmed, Aceil Al-Khatib, Yap Boum, Humberto Debat, Alonso Gurmendi Dunkelberg, Lisa Janicke Hinchliffe, Frith Jarrad, Adam Mastroianni, Patrick Mineault, Charlotte R. Pennington, J. Andrew Pruszynski
Journal: Nature Human Behaviour (2023)
Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases
Authors: Elle M. Weeks, Jacob C. Ulirsch, Nathan Y. Cheng, Brian L. Trippe, Rebecca S. Fine, Jenkai Miao, Tejal A. Patwardhan, Masahiro Kanai, Joseph Nasser, Charles P. Fulco, Katherine C. Tashman, Francois Aguet, Taibo Li, Jose Ordovas-Montanes, Christopher S. Smillie, Moshe Biton, Alex K. Shalek, Ashwin N. Ananthakrishnan, Ramnik J. Xavier, Aviv Regev, Rajat M. Gupta, Kasper Lage, Kristin G. Ardlie, Joel N. Hirschhorn, Eric S. Lander, Jesse M. Engreitz, Hilary K. Finucane
Journal: Nature Genetics (2023)
Emulation of Brain Metabolic Activities Based on a Dynamically Controllable Optical Phantom
Authors: Yuxiang Lin, Cheng Chen, Zhouchen Ma, Nabil Sabor, Yanyan Wei, Tianhong Zhang, Mohamad Sawan, Guoxing Wang, Jian Zhao
Journal: Cyborg and Bionic Systems (2023)

This paper presents a dynamic optical phantom for the simulation of metabolic activities in the brain, and a linear equivalent model is built for control voltage versus substance concentration. A solid–solid dynamic optical phantom is realized by using liquid crystal film as a voltage-controlled light intensity regulator on the surface of basic phantom, which uses epoxy resin as matrix material and nanometer carbon powder and titanium dioxide powder as absorption and scattering dopants, respectively. The dynamic phantom could mimic near-infrared spectrum (NIRS) signals with sampling rate up to 10 Hz, and the maximum simulation errors for oxy-hemoglobin and deoxy-hemoglobin concentrations varying in the range of 1 μmol/l are 7.0% and 17.9%, respectively. Compared with similar solid biomimetic phantoms, the adjustable mimic substance concentration range is extended by an order of magnitude, which meets the simulation requirements of most brain NIRS signals.
Improved polyketide production in C. glutamicum by preventing propionate-induced growth inhibition
Authors: Chunjun Zhan, Namil Lee, Guangxu Lan, Qingyun Dan, Aidan Cowan, Zilong Wang, Edward E. K. Baidoo, Ramu Kakumanu, Bridget Luckie, Rita C. Kuo, Joshua McCauley, Yuzhong Liu, Luis Valencia, Robert W. Haushalter, Jay D. Keasling
Journal: Nature Metabolism (2023)
Studying the genetics of participation using footprints left on the ascertained genotypes
Authors: Stefania Benonisdottir, Augustine Kong
Journal: Nature Genetics (2023)

The trait of participating in a genetic study probably has a genetic component. Identifying this component is difficult as we cannot compare genetic information of participants with nonparticipants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than nonparticipants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. In nonoverlapping samples, a polygenic score constructed from that analysis is significantly associated with educational attainment, body mass index and being invited to a dietary study. The estimated correlation between the genetic components underlying participation in UK Biobank and educational attainment is estimated to be 36.6%-substantial but far from total. Taking participation behaviour into account would improve the analyses of the study data, including those of health traits.
T-prolymphocytic leukemia: TCL1 or MTCP1 rearrangement is not mandatory to establish diagnosis
Authors: Hong Fang, Hannah C. Beird, Sa A. Wang, Andrew F. Ibrahim, Zhenya Tang, Guilin Tang, M. James You, Shimin Hu, Jie Xu, Shaoying Li, C. Cameron Yin, Siba El Hussein, Nhi Le, P. Andrew Futreal, Carlos Bueso-Ramos, Beenu Thakral, Tapan M. Kadia, Rebecca Thornton, Latasha Little, Curtis Gumbs, Xingzhi Song, L. Jeffrey Medeiros, Wei Wang
Journal: Leukemia (2023)
Oxidised IL-33 drives COPD epithelial pathogenesis<i>via</i>ST2-independent RAGE/EGFR signalling complex
Authors: Sam Strickson, Kirsty F. Houslay, Victor A. Negri, Yoichiro Ohne, Tomas Ottosson, Roger B. Dodd, Catherine Chaillan Huntington, Tina Baker, Jingjing Li, Katherine E. Stephenson, Andy J. O'Connor, J. Sophie Sagawe, Helen Killick, Tom Moore, D. Gareth Rees, Sofia Koch, Caroline Sanden, Yixin Wang, Elise Gubbins, Mahboobe Ghaedi, Roland Kolbeck, Saumyaa Saumyaa, Jonas S. Erjefält, Gary P. Sims, Alison A. Humbles, Ian C. Scott, Xavier Romero Ros, E. Suzanne Cohen
Journal: European Respiratory Journal (2023)

Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33 ox ) is thought to limit its activity. We investigated whether IL-33 ox has functional activities that are independent of ST2 in the airway epithelium. Methods In vitro epithelial damage assays and three-dimensional, air–liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33 ox . Transcriptomic changes occurring in healthy ALI cultures treated with IL-33 ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. Results We demonstrate that IL-33 ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro . IL-33 ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33 ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33 ox were enriched in airway epithelia from patients with severe COPD. Conclusions Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.
ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden
Authors: Andrew G. Sharo, Yangyun Zou, Aashish N. Adhikari, Steven E. Brenner
Journal: Genome Medicine (2023)

Abstract Background Curated databases of genetic variants assist clinicians and researchers in interpreting genetic variation. Yet, these databases contain some misclassified variants. It is unclear whether variant misclassification is abating as these databases rapidly grow and implement new guidelines. Methods Using archives of ClinVar and HGMD, we investigated how variant misclassification has changed over 6 years, across different ancestry groups. We considered inborn errors of metabolism (IEMs) screened in newborns as a model system because these disorders are often highly penetrant with neonatal phenotypes. We used samples from the 1000 Genomes Project (1KGP) to identify individuals with genotypes that were classified by the databases as pathogenic. Due to the rarity of IEMs, nearly all such classified pathogenic genotypes indicate likely variant misclassification in ClinVar or HGMD. Results While the false-positive rates of both ClinVar and HGMD have improved over time, HGMD variants currently imply two orders of magnitude more affected individuals in 1KGP than ClinVar variants. We observed that African ancestry individuals have a significantly increased chance of being incorrectly indicated to be affected by a screened IEM when HGMD variants are used. However, this bias affecting genomes of African ancestry was no longer significant once common variants were removed in accordance with recent variant classification guidelines. We discovered that ClinVar variants classified as Pathogenic or Likely Pathogenic are reclassified sixfold more often than DM or DM? variants in HGMD, which has likely resulted in ClinVar’s lower false-positive rate. Conclusions Considering misclassified variants that have since been reclassified reveals our increasing understanding of rare genetic variation. We found that variant classification guidelines and allele frequency databases comprising genetically diverse samples are important factors in reclassification. We also discovered that ClinVar variants common in European and South Asian individuals were more likely to be reclassified to a lower confidence category, perhaps due to an increased chance of these variants being classified by multiple submitters. We discuss features for variant classification databases that would support their continued improvement.
Stable maternal proteins underlie distinct transcriptome, translatome, and proteome reprogramming during mouse oocyte-to-embryo transition
Authors: Hongmei Zhang, Shuyan Ji, Ke Zhang, Yuling Chen, Jia Ming, Feng Kong, Lijuan Wang, Shun Wang, Zhuoning Zou, Zhuqing Xiong, Kai Xu, Zili Lin, Bo Huang, Ling Liu, Qiang Fan, Suoqin Jin, Haiteng Deng, Wei Xie
Journal: Genome biology (2023)

Abstract Background The oocyte-to-embryo transition (OET) converts terminally differentiated gametes into a totipotent embryo and is critically controlled by maternal mRNAs and proteins, while the genome is silent until zygotic genome activation. How the transcriptome, translatome, and proteome are coordinated during this critical developmental window remains poorly understood. Results Utilizing a highly sensitive and quantitative mass spectrometry approach, we obtain high-quality proteome data spanning seven mouse stages, from full-grown oocyte (FGO) to blastocyst, using 100 oocytes/embryos at each stage. Integrative analyses reveal distinct proteome reprogramming compared to that of the transcriptome or translatome. FGO to 8-cell proteomes are dominated by FGO-stockpiled proteins, while the transcriptome and translatome are more dynamic. FGO-originated proteins frequently persist to blastocyst while corresponding transcripts are already downregulated or decayed. Improved concordance between protein and translation or transcription is observed for genes starting translation upon meiotic resumption, as well as those transcribed and translated only in embryos. Concordance between protein and transcription/translation is also observed for proteins with short half-lives. We built a kinetic model that predicts protein dynamics by incorporating both initial protein abundance in FGOs and translation kinetics across developmental stages. Conclusions Through integrative analyses of datasets generated by ultrasensitive methods, our study reveals that the proteome shows distinct dynamics compared to the translatome and transcriptome during mouse OET. We propose that the remarkably stable oocyte-originated proteome may help save resources to accommodate the demanding needs of growing embryos. This study will advance our understanding of mammalian OET and the fundamental principles governing gene expression.
Updated Operational Guidance for Implementing CDC’s Recommendations on Testing for Hepatitis C Virus Infection
Authors: Emily J. Cartwright, Priti Patel, Saleem Kamili, Carolyn Wester
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Current hepatitis C virus (HCV) testing guidance recommends a two-step testing sequence for diagnosis of HCV infection. Performing an HCV RNA test whenever an HCV antibody test is reactive (complete testing) is critical to achieve national HCV elimination goals. When an HCV antibody test is reactive and no HCV RNA test is performed, testing is considered incomplete. Historically, approximately one third of patients have incomplete testing. This update clarifies that all sites performing HCV screening should ensure single-visit sample collection. This approach allows for automatic HCV RNA testing when an HCV antibody test is reactive to avoid incomplete testing. Use of strategies that require multiple visits to collect HCV testing samples should be discontinued. Automatic HCV RNA testing on all HCV antibody reactive samples will increase the percentage of patients with current HCV infection who are linked to care and receive curative antiviral therapy.
<i>Notes from the Field:</i> Emergency Department Visits for Nonfatal Pedal Cyclist Injuries Before and During the COVID-19 Pandemic, United States, 2019–2020
Authors: Livia Navon, Keming Yuan, Laurie Beck
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

During the early months of the COVID-19 pandemic, many jurisdictions implemented stay-at-home orders (1).Vehicle miles traveled (VMT)* in April 2020 declined by 40% compared with VMT in April 2019; annual VMT in 2020 declined by 13% compared with those in 2019 (2).Despite decreased VMT, pedal cyclist traffic crash fatalities increased by 10% from 859 in 2019 to 948 in 2020 (3).In 2021, pedal cyclist fatalities increased to 966, the highest number reported since 1975 (3,4).Given the increase in pedal cyclist fatalities despite the decline in VMT in 2020, emergency department (ED) visits for nonfatal pedal cyclist injuries in 2019 and 2020 were compared.
<i>QuickStats:</i> Life Expectancy at Birth, by Sex — National Vital Statistics System, United States, 2019–2021
Authors: Jiaquan Xu, Arialdi Minino
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

TotalMale FemaleLife expectancy, yrs Sex 0 Life expectancy at birth for the total population declined 2.4 years from 78.8 in 2019 to 76.4 years in 2021.Life expectancy declined for both males and females during this period.For males, life expectancy declined from 76.3 to 73.5 years and for females from 81.4 to 79.3 years.Life expectancy was higher for females than males by 5.1 years in 2019, and that difference increased to 5.8 years in 2021.
Cannabis-Involved Emergency Department Visits Among Persons Aged &lt;25 Years Before and During the COVID-19 Pandemic — United States, 2019–2022
Authors: Douglas R. Roehler, Herschel Smith, Lakshmi Radhakrishnan, Kristin M. Holland, Abigail L. Gates, Alana M. Vivolo-Kantor, Brooke E. Hoots
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

To understand trends in U.S. cannabis-involved emergency department (ED) visits (i.e., those for which cannabis use was documented in the chief complaint or a discharge diagnosis) among young persons aged <25 years during the COVID-19 pandemic, CDC used National Syndromic Surveillance Program data to examine changes in ED visits during 2019-2022. Mean weekly cannabis-involved ED visits among all young persons were higher during the COVID-19 pandemic in 2020, 2021, and 2022, compared with corresponding periods in 2019. Large increases in cannabis-involved ED visits throughout the COVID-19 pandemic compared with prepandemic surveillance periods in 2019 were identified among persons aged ≤10 years. ED visit rates among children and adolescents aged 11-14 years did not differ by sex until the first half of the 2020-21 school year (2020, weeks 37-53), when ED visit rates among females surpassed those among males. Improving clinicians' awareness of rising cannabis-involved ED visits might aid in early diagnosis of cannabis intoxication among young persons. Further, increasing adults' knowledge regarding safe cannabis storage practices, strengthening youths' coping and problem-solving skills through evidence-based prevention programs, and modifying cannabis packaging to decrease appeal to youths might help prevent intentional and unintentional cannabis use.
<i>Notes from the Field:</i> Multipathogen Respiratory Virus Testing Among Primary and Secondary School Students and Staff Members in a Large Metropolitan School District — Missouri, November 2, 2022–April 19, 2023
Authors: Jennifer L. Goldman, Brian R. Lee, Janelle Porter, Anila Deliu, Shannon Tilsworth, Olivia M. Almendares, Sadia Sleweon, Hannah L. Kirking, Rangaraj Selvarangan, Jennifer E. Schuster
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Respiratory virus infections are common in school-aged children (1).Although children spend most of their awake hours in the school setting, few data are available on the prevalence of respiratory viruses in schools.Surveillance for respiratory viruses other than SARS-CoV-2 has not been widely conducted in primary and secondary schools (2).